SUMMARY/ABSTRACT A major goal of neuroscience is to understand how neuromodulatory systems regulate core processes of brain and behavior, from motor function and learning to reward, aversion, attention, and sleep. These systems go awry in schizophrenia and disorders of mood, motor control and cognition. Treatment for these conditions often turns to pharmacological manipulation of neuromodulators and their receptors. Understanding of neuromodulatory circuits has advanced considerably thanks to optogenetics and chemogenetics. But neuromodulation is difficult to crack. A major obstacle is that a single neuromodulator may play many diverse roles because it has multiple receptors, with different functions in different cell locations and different cells within a circuit. Unfortunately, drugs and genetic manipulations cannot typically be targeted or controlled with sufficient spatio-temporal precision to unravel these different functions. We are developing two approaches that provide the needed precision by controlling native, full-length neuromodulatory receptors with photoswitchable tethered ligands (PTLs). Preliminary Iwork demonstrates feasibility of both approaches as applied to two core neuromodulatory receptor families: metabotropic glutamate receptors (mGluRs) and dopamine receptors (DARs). In this proposal, we optimize and expands an approach in which we directly attach PTLs to a specific receptor subtype and develop a new approach that does not touch those receptors, but deliver the PTL to them on a membrane anchor. Because the membrane anchor can be targeted to specific locations within the cell, it can selectively control receptors only at that location, and it can use either broad ligands (which hit all local receptors of that type) or highly selective ligands (to control only one subtype at a time). The tools will be demonstrated in mice and provided to the community as gene delivery vectors, PTLs and transgenic animal lines.